ZYNRELEF BUPIVACAINE and MELOXICAM 400 mg/14mL; 12 mg/14mL Solution — NDC 47426-501-02 (Billing 47426-0501-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action ZYNRELEF is a fixed-dose combination of bupivacaine and meloxicam. Bupivacaine Local anesthetics block the generation and the conduction of nerve impulses presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers.

Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Meloxicam The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro.

Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.2Pharmacodynamics Additional pharmacodynamic data in clinical studies Additional pharmacodynamic data for ZYNRELEF was evaluated in patients undergoing abdominoplasty, Cesarean section, total shoulder arthroplasty, and 1- to 3-level lumbar spinal surgery. Refer to Dosage and Administration for specific doses used for each study [see Dosage and Administration (2.4) ] . Contribution of Meloxicam and Bupivacaine to Activity of ZYNRELEF The contribution of each active ingredient in ZYNRELEF was demonstrated in Phase 2 double-blind, randomized, active- and placebo-controlled clinical studies in subjects undergoing herniorrhaphy or bunionectomy, utilizing ZYNRELEF and formulations of meloxicam alone or bupivacaine alone in the ZYNRELEF vehicle.

In both studies, meloxicam alone demonstrated negligible local analgesia and bupivacaine alone demonstrated greater analgesia compared with placebo through 24 hours post surgery, despite exposure to bupivacaine for approximately 72 hours. Compared with bupivacaine alone in both studies, ZYNRELEF (at the same bupivacaine doses) demonstrated greater and longer analgesia through 24, 48, and 72 hours. Effect on Cardiac Repolarization The effect of ZYNRELEF on cardiac repolarization as assessed by the QTc interval was evaluated following a single administration in patients undergoing surgical procedures.

ZYNRELEF, at single doses up to the maximum recommended dose, did not demonstrate an effect on the QTc interval. Bupivacaine Systemic absorption of local anesthetics, including bupivacaine, produces effects on the cardiovascular and central nervous systems (CNS), which can be serious at toxic blood concentrations [see Warnings and Precautions (5.3) ] . At blood concentrations achieved with normal therapeutic doses, manifestations of CNS stimulation and depression or changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.

Clinical reports and animal research suggest that cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine.

12.3Pharmacokinetics The instillation of ZYNRELEF into the surgical site results in systemic plasma levels of bupivacaine and meloxicam for up to the duration as described in Table 7 for soft tissue surgical procedures and Table 8 for orthopedic surgical procedures. Systemic plasma levels of bupivacaine or meloxicam following application of ZYNRELEF do not correlate with local efficacy. Absorption The rate of systemic absorption of bupivacaine or meloxicam from ZYNRELEF is dependent upon the total dose of drug administered and the vascularity of the administration site.

Pharmacokinetic parameters of bupivacaine and meloxicam after single dose administration by in… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action ZYNRELEF is a fixed-dose combination of bupivacaine and meloxicam. Bupivacaine Local anesthetics block the generation and the conduction of nerve impulses presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers.

Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Meloxicam The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro.

Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3Pharmacokinetics The instillation of ZYNRELEF into the surgical site results in systemic plasma levels of bupivacaine and meloxicam for up to the duration as described in Table 7 for soft tissue surgical procedures and Table 8 for orthopedic surgical procedures. Systemic plasma levels of bupivacaine or meloxicam following application of ZYNRELEF do not correlate with local efficacy. Absorption The rate of systemic absorption of bupivacaine or meloxicam from ZYNRELEF is dependent upon the total dose of drug administered and the vascularity of the administration site.

Pharmacokinetic parameters of bupivacaine and meloxicam after single dose administration by instillation of ZYNRELEF were evaluated following multiple surgical procedures. Descriptive statistics of pharmacokinetic parameters of representative ZYNRELEF doses are provided in Table 7 for soft tissue surgical procedures and Table 8 for orthopedic surgical procedures. Table 7.

Summary of Pharmacokinetic Parameters for Bupivacaine and Meloxicam After Single Dose Administration of ZYNRELEF by Instillation for Soft Tissue Surgical Procedures Active Ingredient Parameter Herniorrhaphy: 300 mg/9 mg ZYNRELEF (N=16) Abdominoplasty: 400 mg/12 mg ZYNRELEF (N=22) Augmentation Mammoplasty: 400 mg/12 mg ZYNRELEF (N=49) Cesarean Section: 400 mg/12 mg ZYNRELEF (N=11) Note: Arithmetic mean (standard deviation) except T max where it is median (min, max). Doses of ZYNRELEF are shown as bupivacaine dose (mg)/meloxicam dose (mg).

NS = not sampled; NR= not reported, since the terminal elimination phase was not adequately characterized in sufficient number of patients. Bupivacaine C max (ng/mL) 271 (147) 382 (149) 710 (246) 291 (70) T max (h) 18 (3, 30) 31 (20, 54) 3.6 (1.3, 35) 24 (1.1, 48) AUC (0-t) AUC (0-t) : 0 to 120 h post-dose for herniorrhaphy, augmentation mammoplasty, and Cesarean section; 0 to 144 h post-dose for abdominoplasty. (h×ng/mL) 15174 (8545) 24411 (10072) 27363 (9227) 17923 (5069) AUC (inf) (h×ng/mL) 15524 (8921) 24930 (10105) 31072 (17998) 17983 (5065) t ½ (h) 16 (9) 20 (8) 25 (20) 10 (2) C 72h (ng/mL) 96 (75) 202 (118) 149 (68) N=48; 127 (56) C 96h (ng/mL) 37 (43) 86 (52) N=21; NS 27 (16) C 144h (ng/mL) NS 16 (11) NS 0.8 (1.0) N=10 Meloxicam C max (ng/mL) 225 (96) 116 (62) 527 (149) 114 (49) T max (h) 54 (24, 96) 24 (4.0, 72) 20 (5.6, 49) 60 (8.5, 73) AUC (0-t) (h×ng/mL) 18721 (7923) 7924 (4197) 30499 (9460) 9710 (4560) AUC (inf) (h×ng/mL) NR 8304 (4422) 41809 (38414) 9778 (4592) t ½ (h) NR 21 (9) 42 (70) 21 (9) C 72h (ng/mL) 197 (95) 70 (44) 214 (105) 86 (43) C 96h (ng/mL) 146 (86) 33 (25) NS 48 (32) C 144h (ng/mL) NS 7.1 (10) NS 11 (12) Table 8.

Summary of Pharmacokinetic Parameters for Bupivacaine and Meloxicam After Single Dose Administration of ZYNRELEF by Instillation for Orthopedic Surgical Procedures Active Ingredient Parameter Bunionectomy: 60 mg/1.8 mg ZYNRELEF (N=17) Total Knee Arthroplasty: 400 mg/12 mg ZYNRELEF (N=53) Total Shoulder Arthroplasty: 400 mg/12 mg ZYNRELEF (N=20) 1-Level Spinal Surgery: 92 mg/2.8 mg ZYNRELEF (N=13) 2- or 3-Level Spinal Surgery: 191 mg/5.7 mg ZYNRELEF (N=13) Note: Arithmetic mean (standard deviation) except T max where it is median (min, max).

Doses of ZYNRELEF are shown as bupivacaine dose (mg)/meloxicam dose (mg). For spinal surgery, ZYNRELEF mean doses for single-level and multilevel surgeries are shown; individual doses ranged from 45 mg/1.4 mg to 248 mg/7.4 mg. NS = not sampled.

Bupivacaine C max (ng/mL) 54 (33) 695 (411) 372 (165) 95 (105) 163 (67) T max (h) 3.0 (1.6, 24) 21 (4, 59) 20 (1.8, 48) 23 (1.9, 38) 24 (4.1, 69) AUC (0-t) AUC (0-t) : 0 to 120 h post-dose for bunionectomy and lumbar spinal decompression; 0 to 144 h post-dose for total knee arthroplasty and total shoulder arthroplasty. (h×ng/mL) 1681 (1154) 35889 (28399) 21132 (12331) 4467 (4977) 8488 (4086) AUC (inf) (h×ng/mL) 1718 (1211) 38173 (29401) N=50; 21193 (12329) 5535 (6091) N=12; 8659 (4288) N=11; t ½ (h) 15 (8) 17 (7) 10 (3) 25 (25) 14 (5) C 72h (ng… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Additional pharmacodynamic data in clinical studies Additional pharmacodynamic data for ZYNRELEF was evaluated in patients undergoing abdominoplasty, Cesarean section, total shoulder arthroplasty, and 1- to 3-level lumbar spinal surgery. Refer to Dosage and Administration for specific doses used for each study [see Dosage and Administration (2.4) ] . Contribution of Meloxicam and Bupivacaine to Activity of ZYNRELEF The contribution of each active ingredient in ZYNRELEF was demonstrated in Phase 2 double-blind, randomized, active- and placebo-controlled clinical studies in subjects undergoing herniorrhaphy or bunionectomy, utilizing ZYNRELEF and formulations of meloxicam alone or bupivacaine alone in the ZYNRELEF vehicle.

In both studies, meloxicam alone demonstrated negligible local analgesia and bupivacaine alone demonstrated greater analgesia compared with placebo through 24 hours post surgery, despite exposure to bupivacaine for approximately 72 hours. Compared with bupivacaine alone in both studies, ZYNRELEF (at the same bupivacaine doses) demonstrated greater and longer analgesia through 24, 48, and 72 hours. Effect on Cardiac Repolarization The effect of ZYNRELEF on cardiac repolarization as assessed by the QTc interval was evaluated following a single administration in patients undergoing surgical procedures.

ZYNRELEF, at single doses up to the maximum recommended dose, did not demonstrate an effect on the QTc interval. Bupivacaine Systemic absorption of local anesthetics, including bupivacaine, produces effects on the cardiovascular and central nervous systems (CNS), which can be serious at toxic blood concentrations [see Warnings and Precautions (5.3) ] . At blood concentrations achieved with normal therapeutic doses, manifestations of CNS stimulation and depression or changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.

Clinical reports and animal research suggest that cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine.

14 CLINICAL STUDIES The efficacy of ZYNRELEF was established in 3 double-blind, controlled studies in patients undergoing bunionectomy (Study 1), unilateral open inguinal herniorrhaphy (Study 2), and total knee arthroplasty (Study 3). Refer to 12.2 for additional supportive pharmacodynamic data for ZYNRELEF [see Pharmacodynamics (12.2) ]. Based on the extrapolation of efficacy of ZYNRELEF across the 3 double-blind, controlled studies in patients undergoing bunionectomy, unilateral open inguinal herniorrhaphy, and total knee arthroplasty, and the pharmacokinetic profiles across surgical procedures with varied characteristics, such as anatomic location, tissue type, length and depth of surgical area, and vascularity, the pharmacokinetic profile and effectiveness of ZYNRELEF are not expected to be clinically significantly different when ZYNRELEF is administered at an appropriate dose in other soft tissue and orthopedic surgical procedures [see Dosage and Administration (2.4) , Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] .

Study 1 In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical trial (NCT03295721), 412 patients undergoing unilateral simple bunionectomy with a lidocaine Mayo block were randomized to 1 of the following 3 treatment groups in a 3:3:2 ratio (respectively): ZYNRELEF 60 mg/1.8 mg, bupivacaine HCl 50 mg, or saline placebo. The mean patient age was 47 years (range 18 to 77) and patients were predominantly female (86%). ZYNRELEF was applied directly into the surgical site, using the cone-shaped applicator, at the end of the procedure, after final irrigation and suction but prior to closure.

Bupivacaine HCl and saline placebo were administered by injection and instillation, respectively. Pain intensity was rated by patients using an 11-point numeric rating scale (NRS) out to 72 hours post-dose. Postoperatively, there was no scheduled pain medication regimen; however, patients were allowed rescue medication as needed, and included oxycodone 10 mg orally every 4 hours, morphine 10 mg IV every 2 hours, and/or acetaminophen 1000 mg orally every 6 hours.

The primary endpoint was the mean area under the curve (AUC) of the NRS pain intensity scores (cumulative pain scores) with activity over the 72-hour period for the ZYNRELEF treatment group compared to the saline placebo treatment group. Secondary endpoints included mean AUC of NRS pain intensity scores over the 72-hour period for the ZYNRELEF treatment group compared to the bupivacaine HCl treatment group, proportion of patients who did not receive opioid analgesia, and total opioid consumption. Patients treated with ZYNRELEF demonstrated a significant reduction in pain intensity compared to those treated with either bupivacaine HCl or saline placebo for up to 72 hours (Figure 1).

A significant proportion of patients treated with ZYNRELEF did not receive opioid analgesia (29%) over 72 hours compared to those treated with either bupivacaine HCl (11%) or saline placebo (2%). Figure 1. Mean Pain Intensity with Activity Over 72 Hours for STUDY 1 (Bunionectomy) Figure 1 Study 2 In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical trial (NCT03237481), 418 patients undergoing unilateral open inguinal herniorrhaphy with mesh under general anesthesia were randomized to 1 of the following 3 treatment groups in a 2:2:1 ratio (respectively): ZYNRELEF 300 mg/9 mg, bupivacaine HCl 75 mg, or saline placebo.

The mean patient age was 49 years (range 18 to 83) and patients were predominantly male (94%). ZYNRELEF was applied directly into the surgical site, using the cone-shaped applicator, at the end of the procedure, following irrigation and suction of each fascial layer but prior to closure. Bupivacaine HCl and saline placebo were administered by injection and instillation, respectively.

Pain intensity was rated by patients using an 11-point NRS out to 72 hours post-dose. Postoperatively, there was n… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, and Impairment of Fertility The maximum recommended human dose (MRHD) of ZYNRELEF is 400 mg and 12 mg of bupivacaine and meloxicam, respectively. Carcinogenesis Bupivacaine Long-term studies in animals to evaluate the carcinogenic potential of ZYNRELEF or bupivacaine have not been conducted. Meloxicam There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) or mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.6 and 3.2 times, respectively, the meloxicam dose level of 12 mg at the MRHD of ZYNRELEF based on BSA comparison).

Mutagenesis Bupivacaine The mutagenic potential of bupivacaine has not been determined. Meloxicam Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility Bupivacaine The effect of ZYNRELEF and bupivacaine on fertility has not been determined.

Meloxicam Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 7.3 and 4 times, respectively, the MRHD based on BSA comparison). In a published study, oral administration of 1 mg/kg (0.8 times the MRHD) meloxicam to male rats for 35 days resulted in decreased sperm count and motility and histopathological evidence of testicular degeneration. The clinical relevance of these findings is unknown.

13.2Animal Toxicology and/or Pharmacology Necrosis and degeneration of cartilage and chondrocytes were observed following intra-articular injection of a single dose of ZYNRELEF in the knee joint of rabbits. Cartilage degeneration was also observed following intra-articular injection of a single dose of ZYNRELEF in the knee joints of dogs.